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Amplification of the lytic potential of effector/memory CD8+ cells by vector-based enhancement of ICAM-1 (CD54) in target cells: implications for intratumoral vaccine therapy.
- Source :
-
Cancer gene therapy [Cancer Gene Ther] 2004 Oct; Vol. 11 (10), pp. 665-80. - Publication Year :
- 2004
-
Abstract
- We demonstrated that enhanced expression of the costimulatory molecules CD80, CD54 and CD48 (designated rF-TRICOM) on target cells, as delivered via a recombinant fowlpox vector, results in an increased state of stimulation of CD8+ T cells, and consequent increased lysis of target cells. CTL studies in conjunction with antibody-blocking studies demonstrated that the enhanced effector activity of these CD8+ T cells is mediated mainly through CD54. Intracellular staining of CD8+ cells that interact with target cells infected with rF-TRICOM showed that they contain higher amounts of perforin and have a higher level of perforin message. Enhanced expression of costimulatory molecules (specifically CD54) on target cells using rF-TRICOM vectors also leads to the formation of stable conjugates/synapses between targets and T cells. The interaction of T cells with target cells that overexpress costimulatory molecules upon infection with rF-TRICOM leads to enhanced signaling through Lck, ZAP70, and STAT-1 in CD8+ T cells and heightened lytic activity of CD8+ cells through the formation of a greater number of immunological synapses. This, in turn, leads to enhanced signaling in T cells. Finally, studies were conducted in mice in which CEA is a self-antigen in an attempt to understand the potential clinical relevancy of intratumoral vaccine therapy. Mice were transplanted subcutaneously with CEA expressing tumors. Intratumoral (i.t.) vaccination was administered 8 days post tumor transplant. Mice vaccinated i.t. with rF-TRICOM demonstrated significantly reduced tumor growth and 40% of the mice had complete tumor regression. The antitumor effects were further improved by the addition of tumor antigen (CEA) in the vaccination by utilizing rF-CEA/TRICOM, with 80% of the mice experiencing complete tumor regression. These studies thus support the concept of intratumoral vaccination employing vectors expressing costimulatory molecules.
- Subjects :
- Adenocarcinoma immunology
Animals
Antigens, CD genetics
B7-1 Antigen genetics
Blotting, Western
CD48 Antigen
Carcinoembryonic Antigen immunology
Cell Line, Tumor
Colonic Neoplasms immunology
Flow Cytometry
Fluorescent Antibody Technique, Indirect
Fowlpox virus genetics
Gene Expression physiology
Intercellular Adhesion Molecule-1 metabolism
Membrane Glycoproteins metabolism
Mice
Mice, Inbred C57BL
Mice, Transgenic
Neoplasm Transplantation
Perforin
Polymerase Chain Reaction
Pore Forming Cytotoxic Proteins
Adenocarcinoma therapy
CD8-Positive T-Lymphocytes immunology
Cancer Vaccines therapeutic use
Colonic Neoplasms therapy
Genetic Vectors
Intercellular Adhesion Molecule-1 genetics
Vaccines, Synthetic therapeutic use
Subjects
Details
- Language :
- English
- ISSN :
- 0929-1903
- Volume :
- 11
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Cancer gene therapy
- Publication Type :
- Academic Journal
- Accession number :
- 15354200
- Full Text :
- https://doi.org/10.1038/sj.cgt.7700741